The LONG-TERM OBJECTIVE of the proposed research is to gain new insights into the fundamental metabolic pathophysiology of sepsis and its progression to septic shock -- with special attention to a novel metabolic role for the reticuloendothelial system (RES) in the pathogenesis of the carbohydrate dyshomeostasis of septic shock. The SPECIFIC AIM is to analyze the interrelation between RES function and glucoregulation in general, and in particular between the hepatic sinusoidal macrophages and parenchymal cells in hepatic glucoregulation in sepsis in rats. Sepsis will be induced using either the cecal ligation and puncture model for fulminating peritonitis, iv E. coli to mimic bacteremia, or lastly endotoxemia with a variety of chemically defined bacterial lipopolysaccharides. METHODOLOGY: Project I will investigate the direct insulinomimetic action of gram-negative lipopolysaccharides -- with special attention (1) to evaluating the range of insulin-like activity of endotoxins on glucose metabolism in adipose tissue, skeletal muscle and especially the liver, (2) to establishing the bioactive moiety of the endotoxin complex, and (3) to evaluating endotoxic interactions with the glucoregulatory hormones -- insulin, glucagon, epinephrine, and glucocorticoids. Project II will evaluate the relation between depressed and stimulated functional states of the RES and glucoregulation in sepsis. Project III will pursue further an original hypothesis developed in this laboratory that the RES in general and hepatic macrophages in particular modulate carbohydrate metabolism via excessive secretion in sepsis of so-called glucoregulatory monokines - macrophage insulin-like activity (MILA) and macrophage-insulin releasing activity (MIRA). In particular, it is proposed (1) to assess the types of macrophages which produce MILA and MIRA and the optimal production conditions - with special attention to hepatic Kupffer cells, (2) to evaluate the effects of peritonitis, bacteremia, and endotoxemia on MILA and MIRA production, and (3) to evaluate the range of glucoregulatory actions of MILA and MIRA -- especially alterations in hepatic glycogenolysis, glycogenesis, glycolysis and gluconeogenesis and their glucoregulatory hormone control. HEALTH RELATEDNESS: These studies should contribute to a greater understanding of compromised metabolic regulation in gram-negative bacteremic shock -- a major public health problem.